An improved synthesis of homoproline and derivatives

Shuman, Robert T.; Ornstein, Paul L.; Paschal, Jonathan W.; Gesellchen, Paul D.

doi:10.1021/jo00289a058

Cited by 82 publications

(41 citation statements)

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“…These data indicated that the cisconfiguration was present in 11 and that all axial orientations were occupied by H-2 and H-4. This result was in full agreement with observations on a similar substrate reported by Shuman et al 10 The carboxylate 11 generated by this synthetic protocol was racemic (DL-cis) due to the nonstereoselective nature of these hydrogenation conditions. It was expected that the coupling of 11 with 7-Cl-MTL would result in a pair of diastereomers, which were confirmed to be separable by silica gel column in later steps.…”

Section: ■ Results and Discussionsupporting

confidence: 93%

“…The solvent was evaporated to afford the desired product 6 (2.3 g, 96%) as a white solid; mp 93−94°C. 6, 127.0, 99.3, 77.8, 31.8, 29.4, 29.2, 29.0, 28.8, 28.1, 22.6, 19.5, 14.0. N-((1S,2S)-2-Chloro-1-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)propyl)-4-(undec-1-ynyl)picolinamide (10). A solution of 6 (201 mg, 0.73 mmol) and triethylamine (186 mg, 1.84 mmol) dissolved in 10 mL of acetonitrile was cooled to 10°C, and isobutylchloroformate (100 mg, 0.73 mmol) was added in one portion.…”

Section: Ms (-Esi): M/z = 2861512 [M − H]mentioning

confidence: 99%

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Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT_2C Receptor Allosteric Modulators

Ding

Bremer

Smith

et al. 2012

ACS Chem. Neurosci.

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Allosteric modulators of the serotonin (5-HT) 5-HT 2C receptor (5-HT 2C R) present a unique drug design strategy to augment the response to endogenous 5-HT in a site-and event-specific manner with great potential as novel central nervous system probes and therapeutics. To date, PNU-69176E is the only reported selective positive allosteric modulator for the 5-HT 2C R. For the first time, an optimized synthetic route to readily access PNU-69176E (1) and its diastereomer 2 has been established in moderate to good overall yields over 10 steps starting from commercially available picolinic acid. This synthetic approach not only enables a feasible preparation of a sufficient amount of 1 for use as a reference compound for secondary pharmacological studies, but also provides an efficient synthesis of key intermediates to develop novel and simplified 5-HT 2C R allosteric modulators. Compound 1 and its diastereomer 2 were functionally characterized in Chinese hamster ovary (CHO) cells stably transfected with the 5-HT 2C R using an intracellular calcium (Ca i 2+ ) release assay. Compound 1 demonstrated efficacy and potency as an allosteric modulator for the 5-HT 2C R with no intrinsic agonist activity. Compound 1 did not alter 5-HT-evoked Ca i 2+ in CHO cells stably transfected with the highly homologous 5-HT 2A R. In contrast, the diastereomer 2 did not alter 5-HT-evoked Ca i 2+ release in 5-HT 2A R-CHO or 5-HT 2C R-CHO cells or exhibit intrinsic agonist activity.KEYWORDS: PNU-69176E, diastereomer, synthesis, allosteric modulator, 5-HT 2C receptor T he serotonin (5-HT) 2C receptor (5-HT 2C R) is implicated in a diversity of physiological functions, such as nociception, motor behavior, endocrine secretion, thermoregulation, appetite modulation, and the control of exchanges between the central nervous system (CNS) and the cerebrospinal fluid.1 This receptor has also been implicated in numerous psychiatric pathologies, and the modulation of 5-HT 2C R function holds a tremendous amount of therapeutic promise for the treatment of diseases of significant unmet medical need, including addiction, anxiety, depression, obesity/ eating disorders, Parkinson's disease, and schizophrenia.Successful development of 5-HT 2C R ligands requires selectivity versus the highly homologous 5-HT 2A R and 5-HT 2B R, as 5-HT 2A/2B R agonists can result in significant CNS (5-HT 2A R) and cardiovascular (5-HT 2B R) adverse effects.3 Allosteric modulators of 5-HT 2C R present a novel and attractive drug design strategy to augment the response to endogenous 5-HT and to achieve high receptor subtype selectivity and specificity with ligand binding to an allosteric site rather than to the orthosteric binding site that binds the endogenous agonist.

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Section: ■ Results and Discussionsupporting

confidence: 93%

Section: Ms (-Esi): M/z = 2861512 [M − H]mentioning

confidence: 99%

Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT_2C Receptor Allosteric Modulators

Ding

Bremer

Smith

et al. 2012

ACS Chem. Neurosci.

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“…Due to its importance in alkaloid and pharmaceutical chemistry, [22] several hydrogenation processes have been developed that employ homogeneous or heterogeneous transition-metal catalysts and often require high pressure of hydrogen. [23] The generality of these catalytic processes is frequently hampered by the lack of selectivity: for example, the hydrogenolysis of aryl-halogen bonds on the carbocyclic ring. As a complementary and alternative method, borohydrides, [24] reducing metals, [25] Hantzsch esters, [26] and silane [27] -based reducing agents were utilized to accomplish the reduction.…”

Section: Resultsmentioning

confidence: 99%

Catalytic Hydrogenation with Frustrated Lewis Pairs: Selectivity Achieved by Size‐Exclusion Design of Lewis Acids

Erős

Nagy

Hasan

et al. 2011

Chemistry A European J

156

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Catalytic hydrogenation that utilizes frustrated Lewis pair (FLP) catalysts is a subject of growing interest because such catalysts offer a unique opportunity for the development of transition-metal-free hydrogenations. The aim of our recent efforts is to further increase the functional-group tolerance and chemoselectivity of FLP catalysts by means of size-exclusion catalyst design. Given that hydrogen molecule is the smallest molecule, our modified Lewis acids feature a highly shielded boron center that still allows the cleavage of the hydrogen but avoids undesirable FLP reactivity by simple physical constraint. As a result, greater latitude in substrate scope can be achieved, as exemplified by the chemoselective reduction of α,β-unsaturated imines, ketones, and quinolines. In addition to synthetic aspects, detailed NMR spectroscopic, DFT, and (2)H isotopic labeling studies were performed to gain further mechanistic insight into FLP hydrogenation.

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“…Diglycidylether of bisphenol A (DGEBA, NPEK-114M) was purchased form Nan Ya Plastics Co. 2-Cyanopyridine, N-(2-hydroxyethyl)piperazine, methyl pyrazine-2-carboxylate, piperazine-2-carboxylic acid (6), 2-pyrazinecarboxylic acid (2), and 2,3-pyrazinedicarboxylic acid (3) were purchased from Sigma-Aldrich Chemical Co. 3-Aminopyrazine-2-carboxylic acid (4), 23 picolinic acid (5), 24 and 3-piperazin-1-yl-propionic acid (7) 25-27 were prepared by following the literature procedure. Their spectroscopic data were shown in the supporting information.…”

Section: Experimental Materialsmentioning

confidence: 99%

“…2-Pyrazinecarboxylic acid (2) and picolinic acid (5) were prepared by reported hydrolysis procedure from 2-cyanopyridine 23 and methyl pyrazine-2-carboxylate. 24 The synthetic route of the generation of 3-piperazin-1-yl-propionic acid (7) was shown in Scheme 2.…”

Section: Synthesismentioning

confidence: 99%

Amphiphatic Piperazine, Pyrazine, and Pyridine Derivaties as the Thermal Latency for Epoxy-Phenolic Resins

et al. 2009

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An improved synthesis of homoproline and derivatives

Cited by 82 publications

References 0 publications

Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT_2C Receptor Allosteric Modulators

Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT_2C Receptor Allosteric Modulators

Catalytic Hydrogenation with Frustrated Lewis Pairs: Selectivity Achieved by Size‐Exclusion Design of Lewis Acids

Amphiphatic Piperazine, Pyrazine, and Pyridine Derivaties as the Thermal Latency for Epoxy-Phenolic Resins

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An improved synthesis of homoproline and derivatives

Cited by 82 publications

References 0 publications

Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT2C Receptor Allosteric Modulators

Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT2C Receptor Allosteric Modulators

Catalytic Hydrogenation with Frustrated Lewis Pairs: Selectivity Achieved by Size‐Exclusion Design of Lewis Acids

Amphiphatic Piperazine, Pyrazine, and Pyridine Derivaties as the Thermal Latency for Epoxy-Phenolic Resins

Contact Info

Product

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Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT_2C Receptor Allosteric Modulators

Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT_2C Receptor Allosteric Modulators